17α-Estradiol: A candidate neuroserm and non-feminizing estrogen for postmenopausal neuronal complications

Kaur, Sukhneeraj P.; Bansal, Seema; Chopra, Kanwaljit

doi:10.1016/j.steroids.2015.01.004

Cited by 15 publications

(11 citation statements)

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“…In the HPC, a great elevation of 5-HT level was found in female Thy1-Ar mice compared to female WT. Although estrogen serves as an antidepressant have been reported by previous publications (Ahokas et al, 2000 ; Kiss et al, 2012 ; Kaur et al, 2015 ), our study first time demonstrated an endogenous estrogen dependent regulation of DA and 5-HT metabolisms in the PFC and HPC. To investigate the estrogen-related DA and 5-HT turnover, we compared DA index and 5-HT index between female Ar +/− or Thy1-Ar mice and female WT mice and found that lacking of endogenous estrogen increased 5-HT index in the PFC and overexpression of brain estrogen reduced 5-HT index in the HPC (Figures 3A,B ).…”

Section: Discussionsupporting

confidence: 46%

Study of Sex Differences in Duloxetine Efficacy for Depression in Transgenic Mouse Models

Jiang

et al. 2017

Front. Cell. Neurosci.

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Clinical evidences show sex differences in risk of developing depressive disorders as well as effect of antidepressants in depression treatment. However, whether such a sex-dependent risk of depression and efficacy of antidepressants is dependent on endogenous estrogen level remain elusive. The aim of this study is to explore the molecular mechanisms of sex differences in antidepressant duloxetine. In the present study, we used genetic knockout or overexpression estrogen-synthesizing enzyme aromatase (Ar) gene as models for endogenous estrogen deficiency and elevation endogenous estrogen, respectively, to examine the anti-depressive efficacy of duloxetine in males and females by force swimming test (FST). We also measured the sex-specific effect of duloxetine on dopamine and serotonin (5-HT) metabolisms in frontal cortex and hippocampus (HPC). Elevation of brain endogenous estrogen in male and female mice showed a reduction of immobility time in FST compared to control mice. Estrogen deficiency in females showed poor response to duloxetine treatment compared to sex-matched wildtype (WT) or aromatase transgenic mice. In contrast, male mice with estrogen deficiency showed same anti-depressive response to duloxetine treatments as aromatase transgenic mice. Our data showed that the sex different effect of endogenous estrogen on duloxetine-induced anti-depressive behavioral change is associated with brain region-specific changes of dopamine (DA) and 5-HT system. Endogenous estrogen exerts antidepressant effects in both males and females. Lacking of endogenous estrogen reduced antidepressive effect of duloxetine in females only. The endogenous estrogen level alters 5-HT system in female mainly, while both DA and 5-HT metabolisms were regulated by endogenous estrogen levels after duloxetine administration.

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Section: Discussionsupporting

confidence: 46%

Study of Sex Differences in Duloxetine Efficacy for Depression in Transgenic Mouse Models

Jiang

et al. 2017

Front. Cell. Neurosci.

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“…Other investigators have found diverse affinities, as well: Kuiper et al (1997) [ 44 ] reported an affinity of 17 α-E2 to ERα of 58% of the relative affinity of 17 β-E2, and 11% to ERβ, while Torand-Allerand et al (2005) [ 26 ] reported an affinity of 17 α-E2 binding to human recombinant ERα and ERβ of 51 and 64% compared to 17 β-E2, respectively. Kaur et al (2015) [ 45 ] indicated an affinity of 17 α-E2 to ERα to be 40-times lower than 17 β-E2. These reports suggest that in an environment where both E2s are present (as is the case in humans and mice in vivo), competition for ER binding may occur; however, since 17 β-E2 has higher binding affinity to both ERs, it tends to exert more biological activity.…”

Section: Discussionmentioning

confidence: 99%

The effects of 17 alpha-estradiol to inhibit inflammation in vitro

et al. 2017

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Background17 Alpha-estradiol (17 α-E2) is a natural, non-feminizing stereoisomer of 17 beta-estradiol (17 β-E2). Whereas much is known about the physiological effects of 17 β-E2, much less is known about 17 α-E2. For example, 17 β-E2 exerts anti-inflammatory effects in neurons and adipocytes through binding and activation of estrogen receptor alpha (ERα); however, if 17 α-E2 has similar effects on inflammation is currently unknown.MethodsTo begin to address this, we analyzed the ability of 17 α-E2 and 17 β-E2 to suppress lipopolysaccharide (LPS)-induced inflammation in vitro using embryonic fibroblast cells (MEF) from wild type and total body ERα (ERKO) male and female mice. Additionally, we further probed if there were sex differences with respect to the effects of E2s using primary pre-adipocyte cells from C57BL/6J male and female mice. Also, we probed mechanistically the effects of E2s in fully differentiated 3T3-L1 cells.ResultsBoth E2s decreased LPS-induced markers of inflammation Tnf-α and Il-6, and increased the anti-inflammatory markers Il-4 and IL-6 receptor (Il-6ra) in MEF cells. To begin to understand the mechanisms by which both E2’s mediate their anti-inflammatory effects, we probed the role of ERα using two methods. First, we used MEF cells from ERKO mice and found reductions in ERα diminished the ability of 17 α-E2 to suppress Tnf-α in female but not in male cells, demonstrating a sexual dimorphism in regard to the role of ERα to mediate 17 α-E2’s effects. Second, we selectively reduced the expression of ERα in 3T3-L1 cells using siRNA and found reductions in ERα diminished the ability of both E2s to suppress Tnf-α and Il-6 expression. Lastly, to determine the mechanisms by which E2s reduce inflammation, we explored the role of NFκB-p65 and found both E2s decreased NFκB-p65 expression.ConclusionsIn conclusion, we demonstrate for the first time that 17 α-E2, as well as 17 β-E2, suppresses inflammation through their effects on ERα and NFκB-p65.Electronic supplementary materialThe online version of this article (10.1186/s13293-017-0151-9) contains supplementary material, which is available to authorized users.

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“…Although 17α-E2 is a naturally-occurring enantiomer to 17β-estradiol (17β-E2), it has been postulated that 17α-E2 signals through a novel uncharacterized receptor [28][29][30][31] as opposed to classical estrogen receptors α (ERα) and β (ERβ); which is due to 17α-E2 having significantly reduced binding affinity for ERα and ERβ as compared to 17β-E2 [32][33][34][35]. For this reason, 17α-E2 is often referred to as a non-feminizing estrogen [31,36,37]. A few studies have suggested that a novel but uncharacterized estrogen receptor, termed ER-X, may mediate 17α-E2 actions in the brain [28][29][30][31], although more recent studies supporting this hypothesis are lacking in the literature.…”

Section: Introductionmentioning

confidence: 99%

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

Mann

Hadad

Holte

et al. 2020

eLife

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Metabolic dysfunction underlies several chronic diseases, many of which are exacerbated by obesity. Dietary interventions can reverse metabolic declines and slow aging, although compliance issues remain paramount. 17α-estradiol treatment improves metabolic parameters and slows aging in male mice. The mechanisms by which 17α-estradiol elicits these benefits remain unresolved. Herein, we show that 17α-estradiol elicits similar genomic binding and transcriptional activation through estrogen receptor α (ERα) to that of 17β-estradiol. In addition, we show that the ablation of ERα completely attenuates the beneficial metabolic effects of 17α-E2 in male mice. Our findings suggest that 17α-E2 may act through the liver and hypothalamus to improve metabolic parameters in male mice. Lastly, we also determined that 17α-E2 improves metabolic parameters in male rats, thereby proving that the beneficial effects of 17α-E2 are not limited to mice. Collectively, these studies suggest ERα may be a drug target for mitigating chronic diseases in male mammals.

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17α-Estradiol: A candidate neuroserm and non-feminizing estrogen for postmenopausal neuronal complications

Cited by 15 publications

References 59 publications

Study of Sex Differences in Duloxetine Efficacy for Depression in Transgenic Mouse Models

Study of Sex Differences in Duloxetine Efficacy for Depression in Transgenic Mouse Models

The effects of 17 alpha-estradiol to inhibit inflammation in vitro

Health benefits attributed to 17α-estradiol, a lifespan-extending compound, are mediated through estrogen receptor α

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